Like Vit Vpu targets host restriction factors for degradation. HIV assembly intimately involves host cell membranes and membrane proteins but major gaps in knowledge remain about the mechanisms and structures of these viral-host interactions. The transmembrane viral protein U (Vpu) is expressed late in the viral life cycle and interferes with host proteins that otherwise restnct virus particle release [28]. Vpu interacts with many proteins in the cell, including tetherin/BST2, CD4, CDIb, NTB-A, and CD40 [28], and acts to degrade or internalize these surface molecules by contacting pTRCP:SCF E3 ligase and adaptor protein 2 (AP2). The HARC Center Proteomics/Genomics Core identified 55 other host factors that either directly interact with Vpu or associate with host-Vpu-host protein complexes [29], including some identified by yeast two-hybrid assays (CAML, MHC-ll-li, and UBP and TASK-1 (an ion channel protein) [30, 31]. These partners provide additional candidates for host restriction factors and targets for degradation. Two phosphorylated serines mediate the Vpu interaction with the substrate recognition domain of pTrCP [32], further emphasizing the importance of PTMs in Vpu-host restriction factor complexes and degradation mechanisms. Full length Vpu forms higher order oligomenc channels in membranes [33]. Mutations in the Vpu transmembrane helix severely reduce infectivity [34, 35], suggesting the potential importance of intramembrane protein interactions. Via an interaction within the plasma membrane bilayer, for example, Vpu antagonizes BST2/tetherin, a single pass integral membrane protein that retains virus particles on the cell surface by attaching to the viral envelope [28, 36-38]. Vpu also hijacks the SCF ubiquitin ligase complex (Cull-Skpl-RbxI-TrCP) and simultaneously interacts with the cytoplasmic tail of CD4 to promote its degradation [39]. Overall, we are poised for the first time to explore these interactions at a mechanistic and structural level.